EP1392714A1 - Steroids as agonists for fxr - Google Patents

Steroids as agonists for fxr

Info

Publication number
EP1392714A1
EP1392714A1 EP02750526A EP02750526A EP1392714A1 EP 1392714 A1 EP1392714 A1 EP 1392714A1 EP 02750526 A EP02750526 A EP 02750526A EP 02750526 A EP02750526 A EP 02750526A EP 1392714 A1 EP1392714 A1 EP 1392714A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
compound according
cholan
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP02750526A
Other languages
German (de)
French (fr)
Other versions
EP1392714B1 (en
Inventor
Roberto Pellicciari
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Intercept Pharmaceuticals Inc
Original Assignee
Intercept Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=23050302&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP1392714(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Intercept Pharmaceuticals Inc filed Critical Intercept Pharmaceuticals Inc
Publication of EP1392714A1 publication Critical patent/EP1392714A1/en
Application granted granted Critical
Publication of EP1392714B1 publication Critical patent/EP1392714B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/12—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic the nitrogen atom of the amino group being further bound to hydrocarbon groups substituted by hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Definitions

  • the present invention relates to Farsnesoid X receptors (FXR). More particularly, the present invention relates to compounds useful as agonists for FXR , pharmaceutical formulations comprising such compounds, and therapeutic use of the same.
  • FXR Farsnesoid X receptors
  • Farnesoid X Receptor is an orphan nuclear receptor initially identified from a rat liver cDNA library (BM. Forman, et al., Cell 81:687- 693 (1995)) that is most closely related to the insect ecdysone receptor.
  • FXR is a member of the nuclear receptor family of ligand- activated transcription factors that includes receptors for the steroid, retinoid, and thyroid hormones (DJ. Mangelsdorf, et al., Cell 83:841-850 (1995)).
  • Northern and in situ analysis show that FXR is most abundantly expressed in the liver, intestine, kidney, and adrenal (BM.
  • FXR binds to DNA as a heterodimer with the 9-cis retinoic acid receptor (RXR).
  • the FXR/RXR heterodimer preferentially binds to response elements composed of two nuclear receptor half sites of the consensus AG(G/T)TCA organized as an inverted repeat and separated by a single nucleotide (IR-1 motif) (BM. Forman, et al., Cell 81:687-693 (1995)).
  • IR-1 motif single nucleotide
  • An early report showed that rat FXR is activated by micromolar concentrations of farnesoids such as farnesol and juvenile hormone (BM. Forman, et al., Cell 81:687-693 (1995)).
  • these compounds failed to activate the mouse and human FXR, leaving the nature of the endogenous FXR ligand in doubt.
  • bile acids that serve as FXR ligands include chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), and the taurine and glycine conjugates of these bile acids.
  • Bile acids are cholesterol metabolites that are formed in the liver and secreted into the duodenum of the intestine, where they have important roles in the solubilization and absorption of dietary lipids and vitamins. Most bile acids ( ⁇ 95%) are subsequently reabsorbed in the ileum and returned to the liver via the enterohepatic circulatory system. The conversion of cholesterol to bile acids in the liver is under feedback regulation: Bile acids down- regulate the transcription of cytochrome P450 7a (CYP7a), which encodes the enzyme that catalyzes the rate limiting step in bile acid biosynthesis.
  • CYP7a cytochrome P450 7a
  • IBABP intestinal bile acid binding protein
  • the present invention provides compounds of formula I:
  • R is ethyl, propyl or allyl, and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
  • the compound of formula (I) is in the form of the glycine or taurine conjugate.
  • the present invention provides 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ - ethyl-5 ⁇ -cholan-24-oic acid and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
  • the present invention provides 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ - propyl-5 ⁇ -cholan-24-oic acid and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
  • the present invention provides 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ - allyl-5 ⁇ -cholan-24-oic acid and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
  • the present invention provides compounds which are FXR agonists.
  • the present invention provides a pharmaceutical formulation comprising a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
  • the present invention provides a method for the prevention or treatment of an FXR mediated disease or condition.
  • the method comprises administering a therapeutically effective amount of a compound of formula (I).
  • the present invention also provides the use of a compound of formula (I) for the preparation of a medicament for the prevention or treatment of an FXR mediated disease or condition.
  • the present invention provides a method for the prevention or treatment of cardiovascular disease.
  • the method comprises administering a therapeutically effective amount of a compound of formula (I).
  • the present invention also provides the use of a compound according to claim 1 for the preparation of a medicament for the prevention or treatment of cardiovascular disease.
  • the cardiovascular disease is atherosclerosis.
  • the present invention provides a method for increasing HDL cholesterol.
  • the method comprises administering a therapeutically effective amount of a compound of formula (I).
  • the present invention also provides the use of a compound according to claim 1 for the preparation of a medicament for increasing HDL-cholesterol.
  • the present invention provides a method for lowering triglycerides.
  • the method comprises administering a therapeutically effective amount of a compound of formula (I).
  • the present invention also provides the use of a compound according to claim 1 for the preparation of a medicament for lowering triglycerides.
  • the present invention provides a method for the prevention or treatment of cholestatic liver disease.
  • the method comprises administering a therapeutically effective amount of a compound of formula (I).
  • the present invention also provides the use of a compound according to claim 1 for the preparation of a medicament for the prevention or treatment of cholestatic liver diseases.
  • the present invention provides a radiolabeled compound of formula (I).
  • the compound of formula (I) is tritiated.
  • the present invention provides a process for preparing a compound of formula (I) and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
  • the process comprises the steps of: a) reacting 3 ⁇ -hydroxy-7-keto-5 ⁇ -cholan-24-oic acid with 3,4- dihydropyrane to prepare 3 ⁇ -tetrahydropyranyloxy-7-keto-5 ⁇ -cholan-24-oic acid; b) reacting 3 ⁇ -tetrahydropyranyloxy-7-keto-5 ⁇ -cholan-24-oic acid with an alkyl bromide of the formula R-Br where R is ethyl, propyl or allyl to prepare a compound of formula (II)
  • Suitable pharmaceutically acceptable salts will be readily determined by one skilled in the art and will include, for example, basic salts such as metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium, and zinc or organic salts made from N,N'-dibenzylethylenediamine, chlorprocaine, choline, diethanolamine, ethylendiamine, meglumine (N-methylglucamine), and procaine.
  • basic salts such as metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium, and zinc or organic salts made from N,N'-dibenzylethylenediamine, chlorprocaine, choline, diethanolamine, ethylendiamine, meglumine (N-methylglucamine), and procaine.
  • Such salts of the compounds of formula (I) may be prepared using conventional techniques, from the compound of Formula (I) by reacting, for example, the appropriate base with the compound of Formula
  • salts of a compound of formula (I) should be pharmaceutically acceptable, but pharmaceutically unacceptable salts may conveniently be used to prepare the corresponding free base or pharmaceutically acceptable salts thereof.
  • solvate is a crystal form containing the compound of formula (I) or a pharmaceutically acceptable salt thereof and either a stoichiometric or a non-stoichiometric amount of a solvent.
  • Solvents include water, methanol, ethanol, or acetic acid.
  • reference to a compound of formula (I) is to any physical form of that compound, unless a particular form, salt or solvate thereof is specified.
  • amino acid conjugates refers to conjugates of the compounds of formula (I) with any suitable amino acid.
  • suitable amino acid conjugates of the compounds of formula (I) will have the added advantage of enhanced integrity in bile or intestinal fluids.
  • suitable amino acids include but are not limited to glycine and taurine.
  • the present invention encompasses the glycine and taurine conjugates of any of the compounds of formula (I).
  • Preferred compounds of formula (I) include compounds selected from the group consisting of 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -ethyl-5 ⁇ -cholan-24-oic acid; 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -propyl-5 ⁇ -cholan-24-oic acid and 3 ⁇ ,7 ⁇ -dihydroxy- 6 ⁇ -allyl-5 ⁇ -cholan-24-oic acid and their pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
  • the compounds of formula (I) are FXR agonists.
  • the term "agonist” refers to compounds which achieve at least 50% activation of FXR relative to CDCA, the appropriate positive control in the assay methods described in PCT Publication No. WO 00/37077 published 29 June 2000 to Glaxo Group Limited, the subject matter of which is incorporated herein by reference in its entirety. More preferably, the compounds of this invention achieve 100% activation of FXR in the scintillation proximity assay or the HTRF assay as described in PCT Publication No. WO 00/37077.
  • the compounds of the formula (I) are useful for a variety of medicinal purposes.
  • the compounds of formula (I) may be used in methods for the prevention or treatment of FXR mediated diseases and conditions.
  • FXR mediated diseases or conditions include cardiovascular diseases including atherosclerosis, arteriosclerosis, hypercholesteremia, and hyperlipidemia.
  • cardiovascular diseases including atherosclerosis, arteriosclerosis, hypercholesteremia, and hyperlipidemia.
  • the compounds of formula (I) are useful in the treatment and prevention of cardiovascular disease including atherosclerosis and hypercholesteremia.
  • the compounds of formula (I) are also useful for increasing HDL-cholesterol, and lowering triglycerides.
  • the compounds of the present invention are useful for the prevention and treatment of cholestatic liver diseases.
  • the compounds of the present invention increase the flow of bile acid. Increased flow of bile acids improves the flux of bile acids from the liver to the intestine. See, C. Sinai, Cell 102: 731-744 (2000).
  • FXR null mice demonstrate that FXR plays a central role in bile acid homeostasis, and is therefore critical to lipid homeostasis by virtue of the regulation of enzymes and transporters that are critical to lipid catabolism and excretion. FXR therefore is an important target for the treatment of a number of choestatic liver disease and other lipid related diseases and conditions.
  • the methods of the present invention are useful for the treatment of mammals generally and particularly humans.
  • the methods of the present invention comprise the step of administering a therapeutically effective amount of the compound of formula (I).
  • therapeutically effective amount refers to an amount of the compound of formula (I) which is sufficient to achieve the stated effect. Accordingly, a therapeutically effective amount of a compound of formula (I) used in the method for the prevention or treatment of FXR mediated diseases or conditions will be an amount sufficient to prevent or treat the FXR mediated disease or condition. Similarly, a therapeutically effective amount of a compound of formula (I) for use in the method for the prophylaxis or treatment of cholestatic liver diseases or increasing bile flow will be an amount sufficient to increase bile flow to the intestine.
  • a typical daily dose for the treatment of FXR mediated diseases and conditions may be expected to lie in the range of from about 0.01 mg/kg to about 100 mg/kg. This dose may be administered as a single unit dose or as several separate unit doses or as a continuous infusion. Similar dosages would be applicable for the treatment of other diseases, conditions and therapies including the prophylaxis and treatment of cholestatic liver diseases.
  • the present invention provides pharmaceutical compositions comprising, as active ingredient, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutical carrier or diluent.
  • These pharmaceutical compositions may be used in the prophylaxis and treatment of the foregoing diseases or conditions and in cardiovascular therapies as mentioned above.
  • the carrier must be pharmaceutically acceptable and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition.
  • the carrier may be a solid or liquid and is preferably formulated as a unit dose formulation, for example, a tablet which may contain from 0.05 to 95% by weight of the active ingredient. If desired other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.
  • Possible formulations include those suitable for oral, sublingual, buccal, parenteral (for example subcutaneous, intramuscular, or intravenous), rectal, topical including transdermal, intranasal and inhalation administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound, but where possible, oral administration is preferred for the prevention and treatment of FXR mediated diseases and conditions.
  • Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in- water or water- in-oil emulsions.
  • Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically a flavoured base, such as sugar and acacia or tragacanth and pastilles comprising the active compound in an inert base, such as gelatine and glycerine or sucrose acacia.
  • a flavoured base such as sugar and acacia or tragacanth
  • pastilles comprising the active compound in an inert base, such as gelatine and glycerine or sucrose acacia.
  • Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood of the intended recipient. Additional formulations suitable for parenteral administration include formulations containing physiologically suitable co- solvents and/or complexing agents such as surfactants and cyclodextrins. Oil-in-water emulsions are also suitable formulations for parenteral formulations. Although such solutions are preferably administered intravenously, they may also be administered by subcutaneous or intramuscular injection.
  • Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient in one or more solid carriers forming the suppository base, for example, cocoa butter.
  • Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils.
  • Suitable carriers for such formulations include petroleum jelly, lanolin, polyethyleneglycols, alcohols, and combinations thereof.
  • Formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound with liquids or finely divided solid carriers or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
  • a tablet may be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • one or more optional ingredients such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • Suitable formulations for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulisers, or insufflators.
  • the particle size of the powder or droplets is typically in the range 0.5 -lO ⁇ m, preferably l-5 ⁇ m, to ensure delivery into the bronchial tree.
  • a particle size in the range 10-500 ⁇ m is preferred to ensure retention in the nasal cavity.
  • Metered dose inhalers are pressurised aerosol dispensers, typically containing a suspension or solution formulation of the active ingredient in a liquefied propellant. During use, these devices discharge the formulation through a valve adapted to deliver a metered volume, typically from 10 to 150 ⁇ l, to produce a fine particle spray containing the active ingredient.
  • Suitable propellants include certain chlorofluorocarbon compounds, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof.
  • the formulation may additionally contain one or more co-solvents, for example, ethanol surfactants, such as oleic acid or sorbitan trioleate, anti-oxidants and suitable flavouring agents.
  • Nebulisers are commercially available devices that transform solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of a compressed gas typically air or oxygen, through a narrow venturi orifice, or by means of ultrasonic agitation.
  • Suitable formulations for use in nebulisers consist of the active ingredient in a liquid carrier and comprising up to 40% w/w of the formulation, preferably less than 20%w/w.
  • the carrier is typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, for example, sodium chloride.
  • Optional additives include preservatives if the formulation is not prepared sterile, for example, methyl hydroxy-benzoate, anti-oxidants, flavouring agents, volatile oils, buffering agents and surfactants.
  • Suitable formulations for administration by insufflation include finely comminuted powders which may be delivered by means of an insufflator or taken into the nasal cavity in the manner of a snuff.
  • the powder is contained in capsules or cartridges, typically made of gelatin or plastic, which are either pierced or opened in situ and the powder delivered by air drawn through the device upon inhalation or by means of a manually- operated pump.
  • the powder employed in the insufflator consists either solely of the active ingredient or of a powder blend comprising the active ingredient, a suitable powder diluent, such as lactose, and an optional surfactant.
  • the active ingredient typically comprises from 0.1 to 100 w/w of the formulation.
  • formulations of the present invention may include other agents known to those skilled in the art of pharmacy, having regard for the type of formulation in issue.
  • formulations suitable for oral administration may include flavouring agents and formulations suitable for intranasal administration may include perfumes.
  • R is ethyl, propyl or allyl.
  • the compounds of the present invention can be prepared by the process comprising a) reacting 3 ⁇ -hydroxy-7-keto-5 ⁇ -cholan-24-oic acid with 3,4-dihydropyrane to prepare 3 ⁇ -tetrahydropyranyloxy-7-keto-5 ⁇ - cholan-24-oic acid; b) reacting 3 ⁇ -tetrahydropyranyloxy-7-keto-5 ⁇ -cholan- 24-oic acid with an alkyl bromide of the formula R-Br where R is ethyl, propyl or allyl to prepare a compound of formula (II); c) reacting the compound of formula (II) with sodium borohydride to prepare a compound of formula (III); d) reacting the compound of formula (III) with sodium hydroxide to prepare the compound of formula (I).
  • the compounds of formula (I) are conveniently prepared by reacting the compounds of formula (III) with sodium hydroxide in a suitable solvent at ambient temperature.
  • suitable solvents include lower alcohols, such as ethanol.
  • the reaction mixture may optionally be acidified with an appropriate acid such as hydrochloric acid.
  • the compounds of formula (III) are conveniently prepared by reacting compounds of formula (II) with sodium borohydride in a suitable solvent at ambient temperature.
  • suitable solvents include lower alcohols such as ethanol.
  • the compounds of formula (II) are conveniently prepared by reacting 3 -tetrahydropyranyloxy-7-keto-5 ⁇ -cholan-24-oic acid with an alkyl bromide of the formula R-Br where R is ethyl, propyl or allyl in a suitable solvent and in the presence of n-Butyl lithium and HMPA in diisopropylamine.
  • Polar solvents such as tetrahydrofuran are useful for conducting the reaction.
  • the reaction is carried out at cold temperatures such as about -70 to -80°C.
  • 3 ⁇ -Tetrahydropyranyloxy-7-keto-5 ⁇ -cholan-24-oic acid can conveniently be prepared from 3 ⁇ -hydroxy-7-keto-5 ⁇ -cholan-24-oic acid by reacting with 3,4-dihydropyrane in p-toluenesulfonic acid.
  • Radiolabeled compounds of formula (I) can be prepared using conventional techniques.
  • radiolabeled compounds of formula (I) can be prepared by reacting the compound of formula (I) with tritium gas in the presence of an appropriate catalyst to produce radiolabeled compounds of formula (I).
  • the compounds of formula (I) are tritiated.
  • radiolabeled compounds of formula (I) are useful in assays for the identification of compounds which interact with FXR such as those described in PCT Publication No. WO 00/37077 already incorporated herein.
  • Ethyl 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -ethyl-5 ⁇ -cholan-24-oate (4) (0.10 g, 0.22 mmol) was dissolved in 15 ml of 96% EtOH and added to 10% NaOH in 96% EtOH (2 ml, 5 mmol). The mixture was refluxed for 4 hours. The mixture was acidified with 3N HCl and extracted with ethyl acetate (3 x 20 ml). The combined organic fractions were washed with a saturated NaCl solution (1 x 50 ml), dried with Na 2 S0 4 and evaporated under vacuum.

Abstract

The invention relates to compounds of formula (I) wherein R is ethyl, propyl or allyl, and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof. The compounds of formula (I) are useful as FXR agonists.

Description

steroides as agonists for fxr
BACKGROUND OF THE INVENTION
The present invention relates to Farsnesoid X receptors (FXR). More particularly, the present invention relates to compounds useful as agonists for FXR , pharmaceutical formulations comprising such compounds, and therapeutic use of the same.
Farnesoid X Receptor (FXR) is an orphan nuclear receptor initially identified from a rat liver cDNA library (BM. Forman, et al., Cell 81:687- 693 (1995)) that is most closely related to the insect ecdysone receptor. FXR is a member of the nuclear receptor family of ligand- activated transcription factors that includes receptors for the steroid, retinoid, and thyroid hormones (DJ. Mangelsdorf, et al., Cell 83:841-850 (1995)). Northern and in situ analysis show that FXR is most abundantly expressed in the liver, intestine, kidney, and adrenal (BM. Forman, et al., Cell 81:687- 693 (1995) and W. Seol, et al., Mol. Endocrinnol. 9:72-85 (1995)). FXR binds to DNA as a heterodimer with the 9-cis retinoic acid receptor (RXR).
■ The FXR/RXR heterodimer preferentially binds to response elements composed of two nuclear receptor half sites of the consensus AG(G/T)TCA organized as an inverted repeat and separated by a single nucleotide (IR-1 motif) (BM. Forman, et al., Cell 81:687-693 (1995)). An early report showed that rat FXR is activated by micromolar concentrations of farnesoids such as farnesol and juvenile hormone (BM. Forman, et al., Cell 81:687-693 (1995)). However, these compounds failed to activate the mouse and human FXR, leaving the nature of the endogenous FXR ligand in doubt. Several naturally-occurring bile acids bind to and activate FXR at physiological concentrations (PCT WO 00/37077, published 29 June 2000)). As discussed therein, the bile acids that serve as FXR ligands include chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), and the taurine and glycine conjugates of these bile acids.
Bile acids are cholesterol metabolites that are formed in the liver and secreted into the duodenum of the intestine, where they have important roles in the solubilization and absorption of dietary lipids and vitamins. Most bile acids (~95%) are subsequently reabsorbed in the ileum and returned to the liver via the enterohepatic circulatory system. The conversion of cholesterol to bile acids in the liver is under feedback regulation: Bile acids down- regulate the transcription of cytochrome P450 7a (CYP7a), which encodes the enzyme that catalyzes the rate limiting step in bile acid biosynthesis. There are data to suggest that FXR is involved in the repression of CYP7a expression by bile acids, although the precise mechanism remains unclear (DW. Russell, Cell 97:539-542 (1999)). In the ileum, bile acids induce the expression of the intestinal bile acid binding protein (IBABP), a cytoplasmic protein which binds bile acids with high affinity and may be involved in their cellular uptake and trafficking. Two groups have now demonstrated that bile acids mediate their effects on IBABP expression through activation of FXR, which binds to an IR-1 type response element that is conserved in the human, rat, and mouse IBABP gene promoters (14; 17). Thus FXR is involved in both the stimulation (IBABP) and the repression (CYP7a) of target genes involved in bile acid and cholesterol homeostasis.
European Patent No. 0 312 867, published 05 May 1992 to Giuliana S.p.A. describes 6-methyl derivatives of natural biliary acids such as ursodeoxycholic acid, ursocholic acid, chenodeoxycholic acid and cholic acid.
BRIEF SUMMARY OF THE INVENTION
According to a first aspect, the present invention provides compounds of formula I:
wherein R is ethyl, propyl or allyl, and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof. In one preferred embodiment, the compound of formula (I) is in the form of the glycine or taurine conjugate. In another aspect, the present invention provides 3α,7α-dihydroxy-6α- ethyl-5β-cholan-24-oic acid and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
In another aspect, the present invention provides 3α,7α-dihydroxy-6α- propyl-5β-cholan-24-oic acid and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
In another aspect, the present invention provides 3α,7α-dihydroxy-6α- allyl-5β-cholan-24-oic acid and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
In another aspect, the present invention provides compounds which are FXR agonists.
In another aspect, the present invention provides a pharmaceutical formulation comprising a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
In another aspect, the present invention provides a method for the prevention or treatment of an FXR mediated disease or condition. The method comprises administering a therapeutically effective amount of a compound of formula (I). The present invention also provides the use of a compound of formula (I) for the preparation of a medicament for the prevention or treatment of an FXR mediated disease or condition.
In another aspect, the present invention provides a method for the prevention or treatment of cardiovascular disease. The method comprises administering a therapeutically effective amount of a compound of formula (I). The present invention also provides the use of a compound according to claim 1 for the preparation of a medicament for the prevention or treatment of cardiovascular disease. In one embodiment, the cardiovascular disease is atherosclerosis.
In another aspect, the present invention provides a method for increasing HDL cholesterol. The method comprises administering a therapeutically effective amount of a compound of formula (I). The present invention also provides the use of a compound according to claim 1 for the preparation of a medicament for increasing HDL-cholesterol.
In another aspect, the present invention provides a method for lowering triglycerides. The method comprises administering a therapeutically effective amount of a compound of formula (I). The present invention also provides the use of a compound according to claim 1 for the preparation of a medicament for lowering triglycerides.
In another aspect, the present invention provides a method for the prevention or treatment of cholestatic liver disease. The method comprises administering a therapeutically effective amount of a compound of formula (I). The present invention also provides the use of a compound according to claim 1 for the preparation of a medicament for the prevention or treatment of cholestatic liver diseases. In another aspect, the present invention provides a radiolabeled compound of formula (I). In one embodiment, the compound of formula (I) is tritiated.
In another aspect, the present invention provides a process for preparing a compound of formula (I) and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof. The process comprises the steps of: a) reacting 3α-hydroxy-7-keto-5β-cholan-24-oic acid with 3,4- dihydropyrane to prepare 3α-tetrahydropyranyloxy-7-keto-5β-cholan-24-oic acid; b) reacting 3α-tetrahydropyranyloxy-7-keto-5β-cholan-24-oic acid with an alkyl bromide of the formula R-Br where R is ethyl, propyl or allyl to prepare a compound of formula (II)
wherein R is ethyl, propyl or allyl; c) reacting the compound of formula (II) with sodium borohydride to prepare a compound of formula (III)
; and d) reacting the compound of formula (III) with sodium hydroxide to prepare the compound of formula (I). Further aspects of the present invention are described in the detailed description of the invention, examples, and claims which follow. DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of formula I: wherein R is ethyl, propyl or allyl, and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
Suitable pharmaceutically acceptable salts according to the present invention will be readily determined by one skilled in the art and will include, for example, basic salts such as metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium, and zinc or organic salts made from N,N'-dibenzylethylenediamine, chlorprocaine, choline, diethanolamine, ethylendiamine, meglumine (N-methylglucamine), and procaine. Such salts of the compounds of formula (I) may be prepared using conventional techniques, from the compound of Formula (I) by reacting, for example, the appropriate base with the compound of Formula
(I)-
When used in medicine, the salts of a compound of formula (I) should be pharmaceutically acceptable, but pharmaceutically unacceptable salts may conveniently be used to prepare the corresponding free base or pharmaceutically acceptable salts thereof.
As used herein, the term "solvate" is a crystal form containing the compound of formula (I) or a pharmaceutically acceptable salt thereof and either a stoichiometric or a non-stoichiometric amount of a solvent.
Solvents, by way of example, include water, methanol, ethanol, or acetic acid. Hereinafter, reference to a compound of formula (I) is to any physical form of that compound, unless a particular form, salt or solvate thereof is specified.
As used herein, the term "amino acid conjugates" refers to conjugates of the compounds of formula (I) with any suitable amino acid. Preferably, such suitable amino acid conjugates of the compounds of formula (I) will have the added advantage of enhanced integrity in bile or intestinal fluids. Suitable amino acids include but are not limited to glycine and taurine. Thus, the present invention encompasses the glycine and taurine conjugates of any of the compounds of formula (I).
Preferred compounds of formula (I) include compounds selected from the group consisting of 3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oic acid; 3α,7α-dihydroxy-6α-propyl-5β-cholan-24-oic acid and 3α,7α-dihydroxy- 6α-allyl-5β-cholan-24-oic acid and their pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
Hereinafter all references to "compounds of formula (I)" refer to compounds of formula (I) as described above together with their and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
Preferably, the compounds of formula (I) are FXR agonists. As used herein, the term "agonist" refers to compounds which achieve at least 50% activation of FXR relative to CDCA, the appropriate positive control in the assay methods described in PCT Publication No. WO 00/37077 published 29 June 2000 to Glaxo Group Limited, the subject matter of which is incorporated herein by reference in its entirety. More preferably, the compounds of this invention achieve 100% activation of FXR in the scintillation proximity assay or the HTRF assay as described in PCT Publication No. WO 00/37077. The compounds of the formula (I) are useful for a variety of medicinal purposes. The compounds of formula (I) may be used in methods for the prevention or treatment of FXR mediated diseases and conditions. FXR mediated diseases or conditions include cardiovascular diseases including atherosclerosis, arteriosclerosis, hypercholesteremia, and hyperlipidemia. In particular, the compounds of formula (I) are useful in the treatment and prevention of cardiovascular disease including atherosclerosis and hypercholesteremia. The compounds of formula (I) are also useful for increasing HDL-cholesterol, and lowering triglycerides.
In addition, the compounds of the present invention are useful for the prevention and treatment of cholestatic liver diseases. The compounds of the present invention increase the flow of bile acid. Increased flow of bile acids improves the flux of bile acids from the liver to the intestine. See, C. Sinai, Cell 102: 731-744 (2000). Essentially, FXR null mice demonstrate that FXR plays a central role in bile acid homeostasis, and is therefore critical to lipid homeostasis by virtue of the regulation of enzymes and transporters that are critical to lipid catabolism and excretion. FXR therefore is an important target for the treatment of a number of choestatic liver disease and other lipid related diseases and conditions.
The methods of the present invention are useful for the treatment of mammals generally and particularly humans.
The methods of the present invention comprise the step of administering a therapeutically effective amount of the compound of formula (I). As used herein, the term "therapeutically effective amount" refers to an amount of the compound of formula (I) which is sufficient to achieve the stated effect. Accordingly, a therapeutically effective amount of a compound of formula (I) used in the method for the prevention or treatment of FXR mediated diseases or conditions will be an amount sufficient to prevent or treat the FXR mediated disease or condition. Similarly, a therapeutically effective amount of a compound of formula (I) for use in the method for the prophylaxis or treatment of cholestatic liver diseases or increasing bile flow will be an amount sufficient to increase bile flow to the intestine.
The amount of a compound of formula (I) or pharmaceutically acceptable salt or solvate thereof, which is required to achieve the desired biological effect will depend on a number of factors such as the use for which it is intended, the means of administration, and the recipient, and will be ultimately at the discretion of the attendant physician or veterinarian. In general, a typical daily dose for the treatment of FXR mediated diseases and conditions, for instance, may be expected to lie in the range of from about 0.01 mg/kg to about 100 mg/kg. This dose may be administered as a single unit dose or as several separate unit doses or as a continuous infusion. Similar dosages would be applicable for the treatment of other diseases, conditions and therapies including the prophylaxis and treatment of cholestatic liver diseases.
Thus in a further aspect the present invention provides pharmaceutical compositions comprising, as active ingredient, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutical carrier or diluent. These pharmaceutical compositions may be used in the prophylaxis and treatment of the foregoing diseases or conditions and in cardiovascular therapies as mentioned above. The carrier must be pharmaceutically acceptable and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition. The carrier may be a solid or liquid and is preferably formulated as a unit dose formulation, for example, a tablet which may contain from 0.05 to 95% by weight of the active ingredient. If desired other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.
Possible formulations include those suitable for oral, sublingual, buccal, parenteral (for example subcutaneous, intramuscular, or intravenous), rectal, topical including transdermal, intranasal and inhalation administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound, but where possible, oral administration is preferred for the prevention and treatment of FXR mediated diseases and conditions.
Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in- water or water- in-oil emulsions.
Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically a flavoured base, such as sugar and acacia or tragacanth and pastilles comprising the active compound in an inert base, such as gelatine and glycerine or sucrose acacia.
Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood of the intended recipient. Additional formulations suitable for parenteral administration include formulations containing physiologically suitable co- solvents and/or complexing agents such as surfactants and cyclodextrins. Oil-in-water emulsions are also suitable formulations for parenteral formulations. Although such solutions are preferably administered intravenously, they may also be administered by subcutaneous or intramuscular injection.
Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient in one or more solid carriers forming the suppository base, for example, cocoa butter. Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. Suitable carriers for such formulations include petroleum jelly, lanolin, polyethyleneglycols, alcohols, and combinations thereof. Formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound with liquids or finely divided solid carriers or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
For example a tablet may be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
Suitable formulations for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulisers, or insufflators.
For pulmonary administration via the mouth, the particle size of the powder or droplets is typically in the range 0.5 -lOμm, preferably l-5μm, to ensure delivery into the bronchial tree. For nasal administration, a particle size in the range 10-500μm is preferred to ensure retention in the nasal cavity.
Metered dose inhalers are pressurised aerosol dispensers, typically containing a suspension or solution formulation of the active ingredient in a liquefied propellant. During use, these devices discharge the formulation through a valve adapted to deliver a metered volume, typically from 10 to 150 μl, to produce a fine particle spray containing the active ingredient. Suitable propellants include certain chlorofluorocarbon compounds, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof. The formulation may additionally contain one or more co-solvents, for example, ethanol surfactants, such as oleic acid or sorbitan trioleate, anti-oxidants and suitable flavouring agents. Nebulisers are commercially available devices that transform solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of a compressed gas typically air or oxygen, through a narrow venturi orifice, or by means of ultrasonic agitation. Suitable formulations for use in nebulisers consist of the active ingredient in a liquid carrier and comprising up to 40% w/w of the formulation, preferably less than 20%w/w. The carrier is typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, for example, sodium chloride. Optional additives include preservatives if the formulation is not prepared sterile, for example, methyl hydroxy-benzoate, anti-oxidants, flavouring agents, volatile oils, buffering agents and surfactants.
Suitable formulations for administration by insufflation include finely comminuted powders which may be delivered by means of an insufflator or taken into the nasal cavity in the manner of a snuff. In the insufflator, the powder is contained in capsules or cartridges, typically made of gelatin or plastic, which are either pierced or opened in situ and the powder delivered by air drawn through the device upon inhalation or by means of a manually- operated pump. The powder employed in the insufflator consists either solely of the active ingredient or of a powder blend comprising the active ingredient, a suitable powder diluent, such as lactose, and an optional surfactant. The active ingredient typically comprises from 0.1 to 100 w/w of the formulation.
In addition to the ingredients specifically mentioned above, the formulations of the present invention may include other agents known to those skilled in the art of pharmacy, having regard for the type of formulation in issue. For example, formulations suitable for oral administration may include flavouring agents and formulations suitable for intranasal administration may include perfumes.
Therefore, according to a further aspect of the present invention, there is provided the use of a compound of formula (I) in the preparation of a medicament for the prevention or treatment of FXR mediated diseases or conditions.
Compounds of the invention can be made according to any suitable method of organic chemistry. According to one method, compounds of formula (I) are prepared using the synthesis process as depicted in Scheme 1 :
Scheme I
wherein R is ethyl, propyl or allyl.
Generally, the compounds of the present invention can be prepared by the process comprising a) reacting 3α-hydroxy-7-keto-5β-cholan-24-oic acid with 3,4-dihydropyrane to prepare 3α-tetrahydropyranyloxy-7-keto-5β- cholan-24-oic acid; b) reacting 3α-tetrahydropyranyloxy-7-keto-5β-cholan- 24-oic acid with an alkyl bromide of the formula R-Br where R is ethyl, propyl or allyl to prepare a compound of formula (II); c) reacting the compound of formula (II) with sodium borohydride to prepare a compound of formula (III); d) reacting the compound of formula (III) with sodium hydroxide to prepare the compound of formula (I).
More particularly, the compounds of formula (I) are conveniently prepared by reacting the compounds of formula (III) with sodium hydroxide in a suitable solvent at ambient temperature. Suitable solvents include lower alcohols, such as ethanol. The reaction mixture may optionally be acidified with an appropriate acid such as hydrochloric acid.
The compounds of formula (III) are conveniently prepared by reacting compounds of formula (II) with sodium borohydride in a suitable solvent at ambient temperature. Suitable solvents include lower alcohols such as ethanol.
The compounds of formula (II) are conveniently prepared by reacting 3 -tetrahydropyranyloxy-7-keto-5β-cholan-24-oic acid with an alkyl bromide of the formula R-Br where R is ethyl, propyl or allyl in a suitable solvent and in the presence of n-Butyl lithium and HMPA in diisopropylamine. Polar solvents such as tetrahydrofuran are useful for conducting the reaction. Preferably, the reaction is carried out at cold temperatures such as about -70 to -80°C.
3α-Tetrahydropyranyloxy-7-keto-5β-cholan-24-oic acid can conveniently be prepared from 3α-hydroxy-7-keto-5β-cholan-24-oic acid by reacting with 3,4-dihydropyrane in p-toluenesulfonic acid.
Pharmaceutically acceptable salts, solvates and amino acid conjugates of the compounds of formula (I) can be prepared from the free base using methods known to those skilled in the art.
The present invention also provides radiolabeled compounds of formula (I). Radiolabeled compounds of formula (I) can be prepared using conventional techniques. For example, radiolabeled compounds of formula (I) can be prepared by reacting the compound of formula (I) with tritium gas in the presence of an appropriate catalyst to produce radiolabeled compounds of formula (I). In one preferred embodiment, the compounds of formula (I) are tritiated.
The radiolabeled compounds of formula (I) are useful in assays for the identification of compounds which interact with FXR such as those described in PCT Publication No. WO 00/37077 already incorporated herein.
The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way, the present invention being defined by the claims. Example: Synthesis of 3α7α-Dihydroxy-6α-ethyl-5β-cholan-24-oic
3α-Tetrahydropyranyloxy-7-keto-5β-cholan-24-oic acid. ?-Toluensulfonic acid (6.0 g, 3.2 mmol) and 3,4-dihydro-2H-pyrane (4.6 g, 54 mmol) were added to a solution of 3α-hydroxy-7-keto-5β-cholan- 24-oic acid (1) (6.0 g, 14.4 mmol) in 120 ml of dioxane. The reaction mixture was stirred at room temperature for 15 min and then was treated with methanol saturated with ammonia until it reached pH of about 8-9. The solvents were removed under vacuum and the residue was extracted with chloroform (200 ml) and washed with a saturated NaHC03 solution (2 x 50 ml). After drying over anhydrous Na2S04 and evaporation under vacuum, the residue was purified by silica gel chromatography. Elution by CHCl3:MeOH (90: 10) yielded 5.4 g (10.4 mmol, 74% yield) of compound 2 as a white solid (mp: 157-159°C). Η-NMR (CDCI3) δ: 0.58 (s, 3H, CH3-18); 0.88 (d, J= 6.1 Hz, 3H, CH3-2I); 1.14 (s, 3H, CH3-19J; 3.3-3.7 (m, 3H, pyr); 3.75-3.95 (m, 1H, pyr); 4.64-4.71 (m, 1H, CH-3).
Ethyl 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oate. n-Butyl lithium (21.1 ml, 1.6M solution in hexane) and HMPA (4.3 ml) were added dropwise at -78°C to a solution of diisopropylamine (4.1 ml,
33.7 mmol) in 250 ml of dry THF. The system was held at-78°C for an additional 30 min and then, 3α-tetrahydropyranyloxy-7-keto-5β-cholan-24- oic acid (2) (5 g, 10.5 mmol) dissolved in 50 ml of dry THF was cooled to - 78°C and added dropwise to the mixture. After 20 minutes ethyl bromide
(7.8 ml, 105 mmol) dissolved in THF (20 ml) was slowly added and the mixture was allowed to come to room temperature overnight. The solvents were removed under vacuum, acidified by 10% HC1 and extracted with ethyl acetate (5 x 200 ml), and washed with a saturated NaCl solution (1 x 200 ml). After drying over anhydrous Na2S04 and evaporation under vacuum, the crude residue was refluxed with a solution of 2N HC1 in EtOH (50 ml) for 12 hours. The residue was evaporated under vacuum and extracted with ethyl acetate (300 ml), washed with a saturated NaHCO3 solution (2 x 100 ml), dried with Na2SO and evaporated under vacuum. The residue was purified by silica gel chromatography; elution by light petroleum: ethyl acetate (70:30) yielded 0.57 g (1.27 mmol, 12% yield) of ethyl 3α-hydroxy-
6α-ethyl-7-keto-5β-cholan-24-oate (3) as an amorphous solid.
Η-NMR (CDCI3) δ: 0.50 (s, 3H, CH3-I 8); 0.69 (t, J= 7.3 Hz, 3H, CH2- CH3); 0.82 (d, J= 6.2 Hz, 3H, CH3-21); 1.06-1.18 (m, 8H, C02 CH2CH?+CH -CH3+CH3- 19) ; 3.36-3.42 (m, 1H, CH-OH), 4.01 (q, J= 7.2, Hz 2H, C02 CH2CH3).
Ethyl 3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oate.
Ethyl 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oate (3) (0.185 g, 0.4 mmol) was dissolved in 30 ml of 96% EtOH and treated with NaBH4 (30 mg, 0.8 mmol). The mixture was stirred at room temperature for 2hours. Water (10 ml) was then added and the mixture was partially concentrated under vacuum and extracted with ethyl acetate (3 x 20 ml). The combined organic fractions were washed with a saturated NaCl solution (1 x 50 ml), dried with Na2S04 and evaporated under vacuum. To give ethyl 3α,7α-dihydroxy-6α-ethyl-5β-cholan- 24-oate (4) (0.15 g, 0.33 mmol, 81% yield) as white solid (mp: 55-57°C).
Η-NMR (CDC13) δ: 0.62 (s, 3H, CH3-18); 0.84-0.92 (m, 9H, CH2-
CH3+CH3-I9+ CH3-2I); 1.22 (t, J= 7.2 Hz, 3H, C02 CH,CH? : 3.30-3.47 (m, 1H, CH-3), 3.66 (brs, 1H, CH-7); 4.08 (q, J= 7.2, Hz 2H, CO2 CH?CH3).
3α,7α-Dihydroxy-6α-ethyl-5β-cholan-24-oic acid.
Ethyl 3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oate (4) (0.10 g, 0.22 mmol) was dissolved in 15 ml of 96% EtOH and added to 10% NaOH in 96% EtOH (2 ml, 5 mmol). The mixture was refluxed for 4 hours. The mixture was acidified with 3N HCl and extracted with ethyl acetate (3 x 20 ml). The combined organic fractions were washed with a saturated NaCl solution (1 x 50 ml), dried with Na2S04 and evaporated under vacuum. The residue was chromatographed on silica gel column; elution by CHCl3:MeOH (95:5) yielded 3α,7α-dihydroxy-6α-methyl-5β-cholan-24-oic acid (6) (0.04 g, 0.095 mmol, 43% yield).
Η-NMR (CDCI3) δ: 0.67 (s, 3H, CH3-18); 0.90-0.96 (m, 9H, CH2- CH3+CH3-19+CH3-21); 2.22-2.46 (2m, 2H, CH2-23); 3.39-3.47 (m, 1H, CH- 3), 3.72 (brs, 1H, CH-7).
13C-NMR (CDC13) δ: 11.65, CH2CH3-6; 11.80, C-18; 18.25, C-21, 20.76, C-11 ; 22.23, CH2CH3-6; 23.14, C-19; 23.69, C-15; 28.17, C-16
30.53, C-2; 30.81, C-22; 30.95, C-23; 33.23, C-9; 33.90, C-10; 35.38, C-20
35.52, C-l ; 35.70, C-4; 39.60, C-12; 40.03, C-5; 41.19, C-6; 42.77, C-13
45.19, C-8; 50.49, C-14; 55.80, C-17; 70.97, C-7; 72.38, C-3; 179.19, C-24.

Claims

1. A compound of formula I:
wherein R is ethyl, propyl or allyl, and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
2. 3α,7α-Dihydroxy-6α-ethyl-5β-cholan-24-oic acid and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
3. 3α,7α-Dihydroxy-6α-propyl-5β-cholan-24-oic acid and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof. 4. 3α,7α-Dihydroxy-6α-allyl-5β-cholan-24-oic acid and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
5. The glycine conjugate of a compound of formula (I) :
wherein R is ethyl, propyl or allyl.
6. The taurine conjugate of a compound of formula (I)
wherein R is ethyl, propyl or allyl.
7. A compound according to claim 1, wherein said compound is an FXR agonist.
8. A pharmaceutical formulation comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
9. A method for the prevention or treatment of an FXR mediated disease or condition comprising administering a therapeutically effective amount of a compound according to claim 1.
10. A method for the prevention or treatment of cardiovascular disease comprising administering a therapeutically effective amount of a compound according to claim 1.
11. The method according to claim 10, wherein said cardiovascular disease is atherosclerosis.
12. A method for increasing HDL cholesterol, said method comprising administering a therapeutically effective amount of a compound according to claim 1.
13. A method for lowering triglycerides, said method comprising administering a therapeutically effective amount of a compound according to claim 1.
14. A method for the prevention or treatment of cholestatic liver disease comprising administering a therapeutically effective amount of a compound according to claim 1. 15. A radiolabeled compound according to claim 1.
16. The compound of claim 15, wherein said compound is tritiated.
17. Use of a compound according to claim 1 for the preparation of a medicament for the prevention or treatment of an FXR mediated disease or condition. 18. Use of a compound according to claim 1 for the preparation of a medicament for the prevention or treatment of cardiovascular disease. 19. Use of a compound according to claim 1 for the preparation of a medicament for the prevention or treatment of atherosclerosis. medicament for increasing HDL-cholesterol.
21. Use of a compound according to claim 1 for the preparation of a medicament for lowering triglycerides.
22. Use of a compound according to claim 1 for the preparation of a medicament for the prevention or treatment of choestatic liver diseases.
23. A process for preparing a compound of formula I:
wherein R is ethyl, propyl or allyl, and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof, said process comprising the steps of: a) reacting 3α-hydroxy-7-keto-5β-cholan-24-oic acid with 3,4- dihydropyrane to prepare 3α-tetrahydropyranyloxy-7-keto-5β-cholan-24-oic acid; b) reacting 3α-tetrahydropyranyloxy-7-keto-5β-cholan-24-oic acid with an alkyl bromide of the formula R-Br where R is ethyl, propyl or allyl to prepare a compound of formula (II)
c) reacting the compound of formula (II) with sodium borohydride to prepare a compound of formula (III) and d) reacting the compound of formula (III) with sodium hydroxide to prepare the compound of formula (I).
EP02750526A 2001-03-12 2002-02-21 Steroids as agonists for fxr Expired - Lifetime EP1392714B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US27495901P 2001-03-12 2001-03-12
US274959P 2001-03-12
PCT/EP2002/001832 WO2002072598A1 (en) 2001-03-12 2002-02-21 Steroids as agonists for fxr

Publications (2)

Publication Number Publication Date
EP1392714A1 true EP1392714A1 (en) 2004-03-03
EP1392714B1 EP1392714B1 (en) 2005-08-31

Family

ID=23050302

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02750526A Expired - Lifetime EP1392714B1 (en) 2001-03-12 2002-02-21 Steroids as agonists for fxr

Country Status (16)

Country Link
US (9) USRE48286E1 (en)
EP (1) EP1392714B1 (en)
JP (2) JP4021327B2 (en)
AT (1) ATE303399T1 (en)
AU (1) AU2002308295B2 (en)
BE (1) BE2017C018I2 (en)
CA (1) CA2440680C (en)
CY (1) CY2017020I1 (en)
DE (1) DE60205891T2 (en)
DK (1) DK1392714T3 (en)
ES (1) ES2248581T3 (en)
FR (1) FR17C0003I2 (en)
IL (2) IL157816A0 (en)
NL (1) NL300877I2 (en)
NO (2) NO326134B1 (en)
WO (1) WO2002072598A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010069604A1 (en) 2008-12-19 2010-06-24 Royal College Of Surgeons In Ireland Treatment of diarrhoea
US7932244B2 (en) 2006-06-27 2011-04-26 Intercept Pharmaceuticals, Inc. Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
WO2014066819A1 (en) 2012-10-26 2014-05-01 Intercept Pharmaceuticals, Inc. Process for preparing bile acid derivatives
WO2017174515A1 (en) 2016-04-04 2017-10-12 Dipharma Francis S.R.L. Method for preparing a farnesoid x receptor agonist
WO2018178260A1 (en) 2017-03-30 2018-10-04 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for reducing persistence and expression of episomal viruses
EP3711762A1 (en) 2013-09-11 2020-09-23 INSERM (Institut National de la Santé et de la Recherche Médicale) A farnesoid x receptor agonsits foruse and pharmaceutical compositions for the treatment of chronic hepatitis b virus infection
WO2021009332A1 (en) 2019-07-18 2021-01-21 Enyo Pharma Method for decreasing adverse-effects of interferon
WO2021144330A1 (en) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of fxr agonists for treating an infection by hepatitis d virus
WO2022152770A1 (en) 2021-01-14 2022-07-21 Enyo Pharma Synergistic effect of a fxr agonist and ifn for the treatment of hbv infection
WO2022229302A1 (en) 2021-04-28 2022-11-03 Enyo Pharma Strong potentiation of tlr3 agonists effects using fxr agonists as a combined treatment

Families Citing this family (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002308295B2 (en) 2001-03-12 2007-08-23 Intercept Pharmaceuticals, Inc. Steroids as agonists for FXR
US6987121B2 (en) * 2002-04-25 2006-01-17 Smithkline Beecham Corporation Compositions and methods for hepatoprotection and treatment of cholestasis
ITMI20021532A1 (en) * 2002-07-12 2004-01-12 Roberto Pellicciari CHEMICAL COMPOUNDS
HUE032928T2 (en) 2004-03-12 2017-11-28 Intercept Pharmaceuticals Inc Treatment of fibrosis using Fxr ligands
US10987362B2 (en) 2004-03-12 2021-04-27 Intercept Pharmaceuticals, Inc. Treatment of fibrosis using FXR ligands
JPWO2005092328A1 (en) * 2004-03-29 2008-02-07 財団法人ヒューマンサイエンス振興財団 FXR activating compound
ITMI20050912A1 (en) 2005-05-19 2006-11-20 Erregierre Spa PROCESS OF PREPARATION OF ACIDS 3-A-YA (B) -DIDROSSI-6-A (B) -ALCHIL-5B-COLANICI
US7618956B2 (en) 2005-05-31 2009-11-17 The Gillette Company Reduction of hair growth
EP1886685A1 (en) 2006-08-11 2008-02-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods, uses and compositions for modulating replication of hcv through the farnesoid x receptor (fxr) activation or inhibition
KR100846441B1 (en) * 2006-12-22 2008-07-16 재단법인서울대학교산학협력재단 Pharmaceutical composition, health food composition, cosmetic composition and farnesoid X-activated receptor inhibitors, containing sterols derivatives
EA017714B1 (en) 2007-01-19 2013-02-28 Интерсепт Фармасьютикалз, Инк. Tgr5 modulators and methods of use thereof
US8338628B2 (en) * 2007-08-28 2012-12-25 City Of Hope Method of synthesizing alkylated bile acid derivatives
BRPI0916735B8 (en) 2008-07-30 2021-05-25 Intercept Pharmaceuticals Inc tgr5 modulating compounds, pharmaceutical compositions comprising them and their uses
SI2698375T1 (en) * 2008-11-19 2018-10-30 Intercept Pharmaceuticals, Inc. TGR5 modulators and method of use thereof
EP3789394A1 (en) 2012-06-19 2021-03-10 Intercept Pharmaceuticals, Inc. Crystalline forms c of obeticholic acid
US9982008B2 (en) 2012-06-19 2018-05-29 Intercept Pharmaceuticals, Inc. Preparation and uses of obeticholic acid
MY170802A (en) * 2012-11-28 2019-08-28 Intercept Pharmaceuticals Inc Treatment of pulmonary disease
MX2015017035A (en) 2013-06-13 2016-04-25 Fast Forward Pharmaceuticals B V Cd40 signalling inhibitor and a.
CN107075515B (en) 2013-11-22 2020-10-30 米纳治疗有限公司 C/EBP alpha compositions and methods of use
CN104876995B (en) * 2014-02-27 2016-09-07 人福医药集团股份公司 The preparation method of chenodeoxycholic acid derivatives
SG11201609403UA (en) * 2014-05-29 2016-12-29 Bar Pharmaceuticals S R L Cholane derivatives for use in the treatment and/or prevention of fxr and tgr5/gpbar1 mediated diseases
EP3006557A1 (en) 2014-10-07 2016-04-13 Heinrich-Heine-Universität Düsseldorf Bile acids for inducing hepatic differentiation
CN105585603B (en) * 2014-10-21 2019-05-24 重庆医药工业研究院有限责任公司 A method of preparing shellfish cholic acid intermediate difficult to understand
EP3215179A4 (en) 2014-11-06 2018-07-25 Enanta Pharmaceuticals, Inc. Bile acid analogs an fxr/tgr5 agonists and methods of use thereof
CN111944006B (en) * 2014-11-17 2021-12-17 正大天晴药业集团股份有限公司 New 7-keto-6 beta-alkyl cholanic acid derivative in preparation of obeticholic acid and application thereof in medical field
EA033445B1 (en) 2014-11-19 2019-10-31 Nzp Uk Ltd 5-beta-6-alkyl-7-hydroxy-3-one steroids as intermediates for the production of steroidal fxr modulators
EP3221333B1 (en) 2014-11-19 2019-07-24 NZP UK Limited 6.alpha.-alkyl-3,7-dione steroids as intermediates for the production of steroidal fxr modulators
MX2017006563A (en) 2014-11-19 2018-01-26 Nzp Uk Ltd 6-alkyl-7-hydroxy-4-en-3-one steroids as intermediates for the production of steroidal fxr modulators.
CA2968310A1 (en) 2014-11-19 2016-05-26 NZP UK Limited 6.alpha.-alkyl-6,7-dione steroids as intermediates for the production of steroidal fxr modulators
US10208081B2 (en) 2014-11-26 2019-02-19 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
RU2017121457A (en) 2014-11-26 2018-12-26 Энанта Фармасьютикалс, Инк. BILIC ACID ANALOGUES AS FXR / TGR5 AGONISTS AND WAYS OF THEIR APPLICATION
US11578097B2 (en) 2014-11-26 2023-02-14 Enanta Pharmaceuticals, Inc. Tetrazole derivatives of bile acids as FXR/TGR5 agonists and methods of use thereof
CN105801653B (en) 2014-12-30 2018-04-17 苏州晶云药物科技有限公司 Crystal form A of shellfish cholic acid difficult to understand and preparation method thereof
CN104672290B (en) * 2015-01-05 2017-06-06 北京普禄德医药科技有限公司 A kind of medicine of disease for preventing or treating FXR mediations and its production and use
KR20170115071A (en) 2015-02-06 2017-10-16 인터셉트 파마슈티컬즈, 인크. Pharmaceutical compositions for combination therapy
KR20170133339A (en) 2015-02-11 2017-12-05 이난타 파마슈티칼스, 인코포레이티드 Bile acid analogs as FXR / TGR5 agonists and methods for their use
CN105985396A (en) * 2015-02-16 2016-10-05 苏州泽璟生物制药有限公司 Deuterated chenodeoxycholic acid derivative and pharmaceutical composition containing same
PT3277286T (en) 2015-03-31 2021-07-01 Enanta Pharm Inc Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof
MX2017012893A (en) 2015-04-07 2018-01-15 Intercept Pharmaceuticals Inc Pharmaceutical compositions for combination therapy.
PE20180690A1 (en) 2015-04-27 2018-04-23 Intercept Pharmaceuticals Inc OBETICOLIC ACID COMPOSITIONS AND METHODS OF USE
CN106290594B (en) * 2015-05-27 2020-07-17 中美华世通生物医药科技（武汉）有限公司 Method for measuring dissolution content of obeticholic acid tablets
CZ2015504A3 (en) 2015-07-16 2017-01-25 Zentiva, K.S. Crystalline forms of obeticholic acid
CN105085597B (en) * 2015-08-28 2017-03-29 成都百裕制药股份有限公司 A kind of preparation method of unformed shellfish cholic acid difficult to understand
CN106478759A (en) * 2015-08-31 2017-03-08 陕西合成药业股份有限公司 Shellfish chlolic acid derivatives difficult to understand and its production and use
KR20180054770A (en) 2015-09-21 2018-05-24 인터셉트 파마슈티컬즈, 인크. How to promote liver regeneration
MX2018003649A (en) 2015-09-24 2018-05-11 Intercept Pharmaceuticals Inc Methods and intermediates for the preparation bile acid derivatives.
CN106589039B (en) * 2015-10-15 2019-12-17 苏州朗科生物技术股份有限公司 preparation method of obeticholic acid and related compound
CN106632564B (en) * 2015-10-30 2021-04-13 苏州泽璟生物制药股份有限公司 Obeticholic acid salt, amorphous substance and pharmaceutical composition thereof
MX2018005520A (en) 2015-11-06 2018-08-01 Intercept Pharmaceuticals Inc Methods for the preparation of obeticholic acid and derivatives thereof.
CN106749466B (en) * 2015-11-23 2019-05-21 南京济群医药科技股份有限公司 A kind of preparation method of high-purity Austria shellfish cholic acid
CN106854229A (en) * 2015-12-08 2017-06-16 陈剑 One class soap, it is prepared and its in application pharmaceutically
WO2017115324A1 (en) 2016-01-01 2017-07-06 Lupin Limited Solid forms of obeticholic acid and processes thereof
KR20180100703A (en) * 2016-01-28 2018-09-11 치아타이 티안큉 파마수티컬 그룹 주식회사 Steroid derivatives FXR function bodies
CN108779141A (en) * 2016-02-10 2018-11-09 雷迪博士实验室有限公司 The amine salt of shellfish cholic acid difficult to understand
WO2017147174A1 (en) 2016-02-23 2017-08-31 Enanta Pharmaceuticals, Inc. Heteroaryl containing bile acid analogs as fxr/tgr5 agonists and methods of use thereof
WO2017147159A1 (en) 2016-02-23 2017-08-31 Enanta Pharmaceuticals, Inc. Deuterated bile acid derivatives as fxr/tgr5 agonists and methods of use thereof
US10323060B2 (en) 2016-02-23 2019-06-18 Enanta Pharmaceuticals, Inc. Benzoic acid derivatives of bile acid as FXR/TGR5 agonists and methods of use thereof
CN109467585A (en) * 2016-03-11 2019-03-15 深圳市塔吉瑞生物医药有限公司 For preventing or treating the disease mediated cholane acid compound of FXR-
CN105541953B (en) * 2016-03-15 2017-11-21 成都市新功生物科技有限公司 A kind of recrystallization purifying method of high-purity Austria shellfish cholic acid
CN107188917A (en) * 2016-03-15 2017-09-22 正大天晴药业集团股份有限公司 Shellfish cholate difficult to understand and its pharmaceutical composition
MX2018011813A (en) 2016-03-28 2019-01-24 Intercept Pharmaceuticals Inc Medicine obtained by combining fxr agonist and arb.
ES2901598T3 (en) 2016-03-31 2022-03-23 Intercept Pharmaceuticals Inc Film-coated tablet having high chemical stability of the active ingredient
AU2017244984A1 (en) 2016-03-31 2018-11-01 Intercept Pharmaceuticals, Inc. Oral preparation having exceptional elutability
EP3228306A1 (en) 2016-04-04 2017-10-11 ratiopharm GmbH Complex compound comprising obeticholic acid and cyclodextrin and pharmaceutical formulation comprising the complex compound
ITUA20162272A1 (en) * 2016-04-04 2017-10-04 Dipharma Francis Srl PROCEDURE FOR THE PREPARATION OF AN AGONIST OF THE FARNESOID RECEPTOR X
CA3020698A1 (en) 2016-04-13 2017-10-19 Intercept Pharmaceuticals, Inc. Methods of treating or preventing hepatocellular carcinoma
TW201738254A (en) 2016-04-19 2017-11-01 英特賽普醫藥品公司 Methods for the preparation of obeticholic acid and derivatives thereof
GB201608776D0 (en) 2016-05-18 2016-06-29 Dextra Lab Ltd Methods and compounds
EA038580B9 (en) * 2016-05-18 2021-10-05 Чиа Тай Тяньцин Фармасьютикал Груп Ко., Лтд. Steroid derivative fxr agonist
GB201608777D0 (en) 2016-05-18 2016-06-29 Dextra Lab Ltd Compounds
WO2017207648A1 (en) 2016-05-31 2017-12-07 Bionice, S.L.U Process and intermediates for the preparation of obeticholic acid and derivatives thereof
US10875887B2 (en) 2016-06-01 2020-12-29 Dr. Reddy's Laboratories Limited. Process for preparation of obeticholic acid
CZ2016385A3 (en) 2016-06-28 2018-01-10 Zentiva, K.S. A method of preparing intermediates for synthesis of obeticholic acid
TWI606565B (en) * 2016-08-31 2017-11-21 金寶電子工業股份有限公司 Package structure and manufacturing method thereof
EP3293196A1 (en) 2016-09-09 2018-03-14 Hexal AG Process for purifying obeticholic acid
JP2019537557A (en) 2016-10-04 2019-12-26 エナンタ ファーマシューティカルズ インコーポレイテッド Isoxazole analogs as FXR agonists and methods of use
EP3305799A3 (en) 2016-10-07 2018-06-20 Lupin Limited Salts of obeticholic acid
JP7057783B2 (en) 2016-11-29 2022-04-20 エナンタ ファーマシューティカルズ インコーポレイテッド Method for preparing sulfonylurea bile acid derivative
CN108264532B (en) * 2016-12-30 2021-02-26 上海现代制药股份有限公司 Preparation method and intermediate of obeticholic acid
US10472386B2 (en) 2017-02-14 2019-11-12 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR agonists and methods of use thereof
MX2019009908A (en) 2017-02-21 2019-10-14 Genfit Combination of a ppar agonist with a fxr agonist.
BR112019020780A2 (en) 2017-04-07 2020-04-28 Enanta Pharm Inc process for preparing sulfonyl carbamate bile acid derivatives
CZ2017298A3 (en) 2017-05-26 2018-12-05 Zentiva, K.S. Amorphous forms of obeticholic acid
CN109134572A (en) * 2017-06-19 2019-01-04 中国科学院上海药物研究所 Chlolic acid derivatives and its preparation method and application
US11189472B2 (en) * 2017-07-17 2021-11-30 Applied Materials, Inc. Cathode assembly having a dual position magnetron and centrally fed coolant
EP3431486A1 (en) 2017-07-18 2019-01-23 Bionice, S.L.U. Process and intermediates for the synthesis of obeticholic acid and derivatives thereof
EP3679139B1 (en) 2017-09-08 2022-11-02 MiNA Therapeutics Limited Stabilized hnf4a sarna compositions and methods of use
US10611793B1 (en) 2017-11-27 2020-04-07 Teva Czech Industries S.R.O. Solid state forms of obeticholic acid salts
WO2019106043A1 (en) 2017-11-29 2019-06-06 Hexal Ag Pharmaceutical composition comprising obeticholic acid
WO2019118571A1 (en) * 2017-12-12 2019-06-20 Enanta Pharmaceuticals, Inc. Isoxazole analogs as fxr agonists and methods of use thereof
US10829486B2 (en) 2018-02-14 2020-11-10 Enanta Pharmacueticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
ES2779985B2 (en) 2019-02-20 2021-03-04 Moehs Iberica Sl 3alpha-tetrahydropyranyloxy-6alpha-ethyl-7alpha-hydroxy-5ß-cholanic acid diethylamine salt
GB201812382D0 (en) 2018-07-30 2018-09-12 Nzp Uk Ltd Compounds
WO2020039449A1 (en) 2018-08-24 2020-02-27 Solara Active Pharma Sciences Limited An improved process for the preparation of obeticholic acid and intermediates used in the process thereof
CN111718388A (en) 2019-03-19 2020-09-29 苏州泽璟生物制药股份有限公司 Preparation method of chenodeoxycholic acid derivative
CN110025591A (en) * 2019-04-29 2019-07-19 郑州泰丰制药有限公司 A kind of Austria's shellfish cholic acid self-emulsifiable preparation and its soft capsule
US11555032B2 (en) 2019-05-13 2023-01-17 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
CN114144185A (en) 2019-05-30 2022-03-04 英特塞普特医药品公司 Pharmaceutical composition comprising an FXR agonist and a fibrate for the treatment of cholestatic liver diseases
CN112341516B (en) * 2020-11-14 2022-07-15 湖南科瑞生物制药股份有限公司 5, 6-epoxy steroid compound and preparation method and application thereof

Family Cites Families (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2615902A (en) 1950-10-24 1952-10-28 Merck & Co Inc Chemical compounds and processes for preparing the same
US3859437A (en) 1972-06-02 1975-01-07 Intellectual Property Dev Corp Reducing cholesterol levels
US4072695A (en) 1972-09-21 1978-02-07 Intellectual Property Development Corporation 3α,7α-Dihydroxy-cholanic acid derivatives
FR2444048B1 (en) 1978-12-15 1981-08-14 Roussel Uclaf
FR2457302A1 (en) 1979-05-23 1980-12-19 Roussel Uclaf NEW PROCESS FOR THE PURIFICATION OF URSODESOXYCHOLIC ACID
IT1165252B (en) 1979-07-12 1987-04-22 Blasinachim Spa PURIFICATION PROCEDURE FOR URSODESOXICOLIC ACID THROUGH NEW DERIVATIVES
DE3003607C2 (en) 1980-02-01 1984-01-05 Dr.-Ing. Rudolf Hell Gmbh, 2300 Kiel Circuit arrangement for partial post-correction of color recognition spaces during color recognition
IT1137459B (en) 1981-04-14 1986-09-10 Erregierre Spa PRODUCTION FOR THE PREPARATION OF HIGH PURITY URSODEOXICOLIC ACID
DE3366932D1 (en) 1982-07-29 1986-11-20 Lehner Ag New derivatives of biliary acids, process for the production thereof and pharmaceutical compositions containing the same
IT1206112B (en) 1983-04-29 1989-04-14 Lehner Ag NEW DERIVATIVES OF BILE ACIDS, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS.
IT1212835B (en) 1983-08-18 1989-11-30 Lehner Ag BILIARY ACID DERIVATIVES, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS.
US4721709A (en) 1984-07-26 1988-01-26 Pyare Seth Novel pharmaceutical compositions containing hydrophobic practically water-insoluble drugs adsorbed on pharmaceutical excipients as carrier; process for their preparation and the use of said compositions
US4892868A (en) 1984-08-17 1990-01-09 Gipharmex, S.P.A. Derivatives of biliary acids, process for the production thereof and corresponding pharmaceutical compositions
IT1196377B (en) 1984-12-21 1988-11-16 Lehner Ag BILIARY ACID DERIVATIVES, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS
IT1223313B (en) 1987-10-20 1990-09-19 Gipharmex Spa BILIARY ACID DERIVATIVES THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
FR2627696B1 (en) 1988-02-26 1991-09-13 Fournier Innovation Synergie NEW GALENIC FORM OF FENOFIBRATE
IT1229570B (en) * 1989-04-17 1991-09-04 Giuliani Spa FLUORATED DERIVATIVES OF BILIARY ACIDS, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
US5175320A (en) 1989-04-17 1992-12-29 Giuliani S.P.A. Fluorinated bile acid derivatives, processes for the preparation thereof and pharmaceutical compositions containing them
US4982868A (en) * 1989-11-07 1991-01-08 Robbins Edward S Iii Bail type pitcher for thin walled container
EP0433899B1 (en) * 1989-12-13 1995-04-12 Mitsubishi Chemical Corporation New pyrazolyl acrylic acid derivatives, useful as systemic fungicides for plant and material protection
JPH04250093A (en) 1991-01-18 1992-09-04 Kanzaki Paper Mfg Co Ltd Thermal recording body
WO1997028149A1 (en) 1996-02-02 1997-08-07 Merck & Co., Inc. Method for raising hdl cholesterol levels
GB9604242D0 (en) 1996-02-28 1996-05-01 Glaxo Wellcome Inc Chemical compounds
GB9606805D0 (en) 1996-03-30 1996-06-05 Glaxo Wellcome Inc Medicaments
AU3552697A (en) 1996-07-12 1998-02-09 Smithkline Beecham Plc Novel treatment of leptine resistance
US6060465A (en) 1997-02-06 2000-05-09 Miljkovic; Dusan Bile acids and their derivatives as glycoregulatory agents
US6008237A (en) 1997-12-19 1999-12-28 Merck & Co., Inc. Arylthiazolidinedione derivatives
US6200995B1 (en) 1998-01-29 2001-03-13 Tularik Inc. PPAR-γ modulators
US6639057B1 (en) * 1998-03-26 2003-10-28 Kyowa Hakko Kogyo Co., Ltd. Monoclonal antibody against human telomerase catalytic subunit
EP1137940A4 (en) 1998-10-23 2004-06-02 Glaxo Group Ltd Assays for ligands for nuclear receptors
JP2002529740A (en) 1998-11-09 2002-09-10 アセロジエニクス・インコーポレイテツド Methods and compositions for lowering plasma cholesterol levels
UA74141C2 (en) 1998-12-09 2005-11-15 Дж.Д. Сірл Енд Ко. Oral pharmaceutical compositions comprising micronized eplerenone (variants), method for its production and method for treating aldosterone-mediated states (variants)
ES2326850T3 (en) 1998-12-23 2009-10-20 Glaxo Group Limited TESTS FOR NUCLEAR RECEPTORS LIGANDOS.
US6465258B1 (en) 1999-01-07 2002-10-15 Tularik, Inc. FXR receptor-mediated modulation cholesterol metabolism
DE60029029T2 (en) 1999-03-26 2007-06-14 City Of Hope, Duarte Screen for FXR receptor modulators
US20020132223A1 (en) 1999-03-26 2002-09-19 City Of Hope Methods for modulating activity of the FXR nuclear receptor
EP1473042B1 (en) 1999-03-26 2006-06-21 City of Hope Screening for FXR receptor modulators
CN1368884A (en) 1999-06-11 2002-09-11 阿勒根销售公司 Method for modulating FXR receptor activity
US6906057B1 (en) 1999-06-11 2005-06-14 Allergan, Inc. Methods for modulating FXR receptor activity
US6559188B1 (en) 1999-09-17 2003-05-06 Novartis Ag Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes
JP2003525217A (en) 1999-10-22 2003-08-26 メルク エンド カムパニー インコーポレーテッド Obesity treatment drugs
US6627636B2 (en) 2000-06-15 2003-09-30 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US6777446B2 (en) 2000-09-05 2004-08-17 Tularik, Inc. FXR modulators
US20020119958A1 (en) 2001-02-13 2002-08-29 Shinichiro Tojo Therapeutic agent for hyperlipidemia
AU2002308295B2 (en) 2001-03-12 2007-08-23 Intercept Pharmaceuticals, Inc. Steroids as agonists for FXR
US7354726B2 (en) 2001-04-12 2008-04-08 Takeda Pharmaceutical Company Limited Screening method
EP1423113A4 (en) 2001-08-13 2007-04-18 Phenex Pharmaceuticals Ag Nr1h4 nuclear receptor binding compounds
WO2003016280A1 (en) 2001-08-13 2003-02-27 Lion Bioscience Ag Nr1h4 nuclear receptor binding compounds
EP1285914B1 (en) 2001-08-13 2007-12-19 PheneX Pharmaceuticals AG Nr1h4 nuclear receptor binding compounds
US7112340B2 (en) 2001-10-19 2006-09-26 Baxter International Inc. Compositions of and method for preparing stable particles in a frozen aqueous matrix
US20030144360A1 (en) 2001-11-19 2003-07-31 Allergan Sales, Inc. Composition and method for modulating BAR/FXR receptor activity
AU2003225903A1 (en) 2002-03-21 2003-10-08 Curagen Corporation Methods of using farnesoid x receptor (fxr) agonists
EP1494533A2 (en) 2002-04-12 2005-01-12 The University of Chicago Farnesoid x-activated receptor agonists
US6987121B2 (en) 2002-04-25 2006-01-17 Smithkline Beecham Corporation Compositions and methods for hepatoprotection and treatment of cholestasis
ITMI20021532A1 (en) 2002-07-12 2004-01-12 Roberto Pellicciari CHEMICAL COMPOUNDS
US7319109B2 (en) 2002-11-22 2008-01-15 Smith Kline Beecham Corporation Farnesoid X receptor agonists
US6993380B1 (en) 2003-06-04 2006-01-31 Cleveland Medical Devices, Inc. Quantitative sleep analysis method and system
EP1696910A4 (en) 2003-09-26 2009-12-09 Smithkline Beecham Corp Compositions and methods for treatment of fibrosis
EP1568706A1 (en) 2004-02-26 2005-08-31 Intercept Pharmaceuticals, Inc. Novel steroid agonist for FXR
WO2005092369A2 (en) 2004-03-11 2005-10-06 Fresenius Kabi Deutschland Gmbh Conjugates of hydroxyethyl starch and erythropoietin
HUE032928T2 (en) 2004-03-12 2017-11-28 Intercept Pharmaceuticals Inc Treatment of fibrosis using Fxr ligands
US20060252670A1 (en) 2004-10-14 2006-11-09 Intercept Pharmaceuticals Inc. Method of reducing drug-induced adverse side effects in a patient
ITMI20050912A1 (en) 2005-05-19 2006-11-20 Erregierre Spa PROCESS OF PREPARATION OF ACIDS 3-A-YA (B) -DIDROSSI-6-A (B) -ALCHIL-5B-COLANICI
CN101395170A (en) 2006-02-14 2009-03-25 英特塞普特药品公司 Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
CA2656320C (en) 2006-06-27 2015-04-28 Intercept Pharmaceuticals, Inc. Bile acid derivatives as fxr ligands for the prevention or treatment of fxr-mediated diseases or conditions
WO2008062475A2 (en) 2006-10-26 2008-05-29 Cadila Healthcare Limited Pharmaceutical compositions of ursodiol
EA017714B1 (en) 2007-01-19 2013-02-28 Интерсепт Фармасьютикалз, Инк. Tgr5 modulators and methods of use thereof
EP1947108A1 (en) 2007-01-19 2008-07-23 Intercept Pharmaceuticals, Inc. TGR5 modulators and methods of use thereof
US8338628B2 (en) 2007-08-28 2012-12-25 City Of Hope Method of synthesizing alkylated bile acid derivatives
SI2698375T1 (en) 2008-11-19 2018-10-30 Intercept Pharmaceuticals, Inc. TGR5 modulators and method of use thereof
SG10201401712QA (en) 2009-04-24 2014-08-28 Iceutica Pty Ltd Method for the production of commercial nanoparticle and microparticle powders
EP2468762A1 (en) 2010-11-30 2012-06-27 Dr. Falk Pharma Gmbh Optimized synthesis of pure, non-polymorphic, crystalline bile acids with defined particle size
WO2013037482A1 (en) 2011-09-15 2013-03-21 Phenex Pharmaceuticals Ag Farnesoid x receptor agonists for cancer treatment and prevention
FR2981572B1 (en) 2011-10-21 2018-01-19 Inopharm Limited PHARMACEUTICAL COMPOSITIONS OF URSODESOXYCHOLIC ACID
EP3789394A1 (en) 2012-06-19 2021-03-10 Intercept Pharmaceuticals, Inc. Crystalline forms c of obeticholic acid
DK3848038T3 (en) 2013-05-14 2023-02-06 Intercept Pharmaceuticals Inc 11-Hydroxyl-6-substituted derivatives of bile acids and their amino acid conjugates as farnesoid X receptor modulates.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02072598A1 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7932244B2 (en) 2006-06-27 2011-04-26 Intercept Pharmaceuticals, Inc. Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
US8546365B2 (en) 2006-06-27 2013-10-01 Intercept Pharmaceuticals, Inc. Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
US9090652B2 (en) 2006-06-27 2015-07-28 Intercept Pharmaceuticals, Inc. Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
US9763964B2 (en) 2006-06-27 2017-09-19 Intercept Pharmaceuticals, Inc. Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
WO2010069604A1 (en) 2008-12-19 2010-06-24 Royal College Of Surgeons In Ireland Treatment of diarrhoea
WO2014066819A1 (en) 2012-10-26 2014-05-01 Intercept Pharmaceuticals, Inc. Process for preparing bile acid derivatives
EP3711762A1 (en) 2013-09-11 2020-09-23 INSERM (Institut National de la Santé et de la Recherche Médicale) A farnesoid x receptor agonsits foruse and pharmaceutical compositions for the treatment of chronic hepatitis b virus infection
WO2017174515A1 (en) 2016-04-04 2017-10-12 Dipharma Francis S.R.L. Method for preparing a farnesoid x receptor agonist
WO2018178260A1 (en) 2017-03-30 2018-10-04 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for reducing persistence and expression of episomal viruses
WO2021009332A1 (en) 2019-07-18 2021-01-21 Enyo Pharma Method for decreasing adverse-effects of interferon
WO2021144330A1 (en) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of fxr agonists for treating an infection by hepatitis d virus
WO2022152770A1 (en) 2021-01-14 2022-07-21 Enyo Pharma Synergistic effect of a fxr agonist and ifn for the treatment of hbv infection
WO2022229302A1 (en) 2021-04-28 2022-11-03 Enyo Pharma Strong potentiation of tlr3 agonists effects using fxr agonists as a combined treatment

Also Published As

Publication number Publication date
CA2440680C (en) 2010-06-01
NO2017022I1 (en) 2017-05-26
DK1392714T3 (en) 2006-01-09
NO2017022I2 (en) 2018-08-20
US9732117B2 (en) 2017-08-15
ATE303399T1 (en) 2005-09-15
DE60205891D1 (en) 2005-10-06
CY2017020I2 (en) 2017-11-14
AU2002308295B2 (en) 2007-08-23
US8377916B2 (en) 2013-02-19
JP2004519492A (en) 2004-07-02
FR17C0003I1 (en) 2017-07-21
ES2248581T3 (en) 2006-03-16
FR17C0003I2 (en) 2018-05-25
US20070142340A1 (en) 2007-06-21
IL157816A (en) 2009-05-04
US20150166598A1 (en) 2015-06-18
NL300877I2 (en) 2017-06-22
US20120053163A1 (en) 2012-03-01
US7138390B2 (en) 2006-11-21
US20160152657A1 (en) 2016-06-02
NO326134B1 (en) 2008-10-06
US8058267B2 (en) 2011-11-15
US8969330B2 (en) 2015-03-03
IL157816A0 (en) 2004-03-28
US10421772B2 (en) 2019-09-24
US7786102B2 (en) 2010-08-31
US20100022498A1 (en) 2010-01-28
BE2017C018I2 (en) 2021-02-04
JP4021327B2 (en) 2007-12-12
NO20034011L (en) 2003-11-12
JP2007269815A (en) 2007-10-18
DE60205891T2 (en) 2006-06-22
NO20034011D0 (en) 2003-09-11
CY2017020I1 (en) 2017-11-14
USRE48286E1 (en) 2020-10-27
US20140024631A1 (en) 2014-01-23
US20190300564A9 (en) 2019-10-03
CA2440680A1 (en) 2002-09-19
WO2002072598A1 (en) 2002-09-19
US20050080064A1 (en) 2005-04-14
US20170305961A1 (en) 2017-10-26
EP1392714B1 (en) 2005-08-31

Similar Documents

Publication Publication Date Title
US10421772B2 (en) Steroids as agonists for FXR
AU2002308295A1 (en) Steroids as agonists for FXR
US7812011B2 (en) Steroid agonist for FXR
US7858608B2 (en) Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
WO2004007521A2 (en) Bile acid derivatives as agonists of the farnesoid x receptor
AU2007265457A1 (en) Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20031003

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

17Q First examination report despatched

Effective date: 20040428

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: INTERCEPT PHARMACEUTICALS, INC.

RIN1 Information on inventor provided before grant (corrected)

Inventor name: PELLICCIARI, ROBERTO

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 60205891

Country of ref document: DE

Date of ref document: 20051006

Kind code of ref document: P

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20050403625

Country of ref document: GR

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: ISLER & PEDRAZZINI AG

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2248581

Country of ref document: ES

Kind code of ref document: T3

ET Fr: translation filed
PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20060601

REG Reference to a national code

Ref country code: DE

Ref legal event code: 8364

Ref document number: 60205891

Country of ref document: DE

REG Reference to a national code

Ref country code: CH

Ref legal event code: PCAR

Free format text: ISLER & PEDRAZZINI AG;POSTFACH 1772;8027 ZUERICH (CH)

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 15

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 16

REG Reference to a national code

Ref country code: FI

Ref legal event code: SPCF

Spc suppl protection certif: C20170024

REG Reference to a national code

Ref country code: CH

Ref legal event code: PCOW

Free format text: NEW ADDRESS: 10 HUDSONS YARDS, 37TH FL, NEW YORK, NY 10001 (US)

REG Reference to a national code

Ref country code: IT

Ref legal event code: SPCF

Ref document number: 502005901363537

Country of ref document: IT

Free format text: PRODUCT NAME: ACIDO OBETICOLICO(OCALIVA); AUTHORISATION NUMBER(S) AND DATE(S): EU/1/16/1139, 20161215

Spc suppl protection certif: 132017000061826

REG Reference to a national code

Ref country code: FR

Ref legal event code: CP

Free format text: PRODUCT NAME: ACIDE OBETICHOLIQUE; REGISTRATION NO/DATE: EU/1/16/1139 20161212

Spc suppl protection certif: 17C0003

Filing date: 20170607

Extension date: 20270220

Ref country code: SE

Ref legal event code: SPCF

Free format text: PRODUCT NAME: OBETICHOLIC ACID; REG. NO/DATE: EU/1/16/1139 20161215

Spc suppl protection certif: 1790020-0

Ref country code: FR

Ref legal event code: CP

Free format text: PRODUCT NAME: ACIDE OBETICHOLIQUE; REGISTRATION NO/DATE: EU/1/16/1139 20161212

Spc suppl protection certif: 17C0003

Filing date: 20170607

REG Reference to a national code

Ref country code: IE

Ref legal event code: SPCF

Free format text: PRODUCT NAME: OBETICHOLIC ACID; REGISTRATION NO/DATE: EU/1/16/1139/001 EU/1/16/1139/002 20161212

Spc suppl protection certif: 2017/019

Filing date: 20170523

REG Reference to a national code

Ref country code: GB

Ref legal event code: CTFF

Free format text: PRODUCT NAME: OBETICHOLIC ACID; REGISTERED: UK EU/1/16/1139 20161215

Spc suppl protection certif: SPC/GB17/033

Filing date: 20170520

Ref country code: NL

Ref legal event code: SPCF

Free format text: PRODUCT NAME: OBETICHOLZUUR; REGISTRATION NO/DATE: EU/1/16/1139 20161215

Spc suppl protection certif: 300877

Filing date: 20170609

Expiry date: 20220220

Extension date: 20270220

Ref country code: NL

Ref legal event code: SPCG

Free format text: PRODUCT NAME: OBETICHOLZUUR; REGISTRATION NO/DATE: EU/1/16/1139 20161215

Spc suppl protection certif: 300877

Filing date: 20170609

Expiry date: 20220220

Extension date: 20270220

Effective date: 20170622

REG Reference to a national code

Ref country code: DK

Ref legal event code: CTFF

Free format text: PRODUCT NAME: OBETICHOLIC ACID; REG. NO/DATE: EU/1/16/1139 20161215

Spc suppl protection certif: CA 2017 00025

Filing date: 20170607

Expiry date: 20220221

Extension date: 20270221

REG Reference to a national code

Ref country code: FR

Ref legal event code: CA

Effective date: 20170526

REG Reference to a national code

Ref country code: DE

Ref legal event code: R065

Ref document number: 60205891

Country of ref document: DE

Free format text: PRODUCT NAME: OBETICHOLSAEURE (OBETICHOLIC ACID); REGISTRATION NO/DATE: EU/1/16/1139 20161212

Spc suppl protection certif: 122017000034

Filing date: 20170522

Expiry date: 20220222

Ref country code: DE

Ref legal event code: R065

Ref document number: 60205891

Country of ref document: DE

Free format text: PRODUCT NAME: OBETICHOLSAEURE; REGISTRATION NO/DATE: EU/1/16/1139 20161212

Spc suppl protection certif: 122017000034

Filing date: 20170522

Expiry date: 20220222

Extension date: 20270221

REG Reference to a national code

Ref country code: AT

Ref legal event code: SPCF

Ref document number: 303399

Country of ref document: AT

Kind code of ref document: T

Free format text: PRODUCT NAME: OBETICHOLSAEURE, DESSEN PHARMAZEUTISCH AKZEPTABLEN SALZE, SOLVATE ODER AMINOSAEURE-KONJUGATE; REGISTRATION NO/DATE: EU/1/16/1139 20161212

Spc suppl protection certif: 23/2017

Filing date: 20170608

Effective date: 20170715

REG Reference to a national code

Ref country code: LU

Ref legal event code: SPCF

Free format text: PRODUCT NAME: ACIDE OBETICHOLIQUE ET SES DERIVES PHARMACEUTIQUEMENT ACCEPTABLES (OCALIVA); AUTHORISATION NUMBER AND DATE: EU/1/16/1139 20161215

Spc suppl protection certif: LUC00018

Filing date: 20170522

Expiry date: 20220221

Extension date: 20270221

REG Reference to a national code

Ref country code: LU

Ref legal event code: SPCG

Free format text: PRODUCT NAME: ACIDE OBETICHOLIQUE ET SES DERIVES PHARMACEUTIQUEMENT ACCEPTABLES (OCALIVA); AUTHORISATION NUMBER AND DATE: EU/1/16/1139 20161215

Spc suppl protection certif: LUC00018

Filing date: 20170522

Expiry date: 20220221

Extension date: 20270221

Effective date: 20170803

REG Reference to a national code

Ref country code: DK

Ref legal event code: CTFG

Free format text: PRODUCT NAME: OBETICHOLIC ACID; REG. NO/DATE: EU/1/16/1139 20161215

Spc suppl protection certif: CR 2017 00025

Filing date: 20170607

Expiry date: 20220221

Extension date: 20270221

REG Reference to a national code

Ref country code: IT

Ref legal event code: SPCG

Ref document number: 502005901363537

Country of ref document: IT

Free format text: PRODUCT NAME: ACIDO OBETICOLICO(OCALIVA); AUTHORISATION NUMBER(S) AND DATE(S): EU/1/16/1139, 20161215

Spc suppl protection certif: 132017000061826

Extension date: 20270221

REG Reference to a national code

Ref country code: AT

Ref legal event code: SPCG

Ref document number: 303399

Country of ref document: AT

Kind code of ref document: T

Free format text: PRODUCT NAME: OBETICHOLSAEURE, DESSEN PHARMAZEUTISCH AKZEPTABLEN SALZE, SOLVATE ODER AMINOSAEURE-KONJUGATE; REGISTRATION NO/DATE: EU/1/16/1139 20161212

Spc suppl protection certif: 23/2017

Filing date: 20170608

Expiry date: 20220221

Extension date: 20270221

Effective date: 20171115

REG Reference to a national code

Ref country code: SE

Ref legal event code: SPCG

Free format text: PRODUCT NAME: OBETICHOLIC ACID; REG. NO/DATE: EU/1/16/1139 20161215

Spc suppl protection certif: 1790020-0

Expiry date: 20220222

Extension date: 20270221

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 17

REG Reference to a national code

Ref country code: DE

Ref legal event code: R067

Ref document number: 60205891

Country of ref document: DE

Free format text: PRODUCT NAME: OBETICHOLSAEURE; REGISTRATION NO/DATE: EU/1/16/1139 20161212

Spc suppl protection certif: 122017000034

Filing date: 20170522

Expiry date: 20220222

Extension date: 20270221

REG Reference to a national code

Ref country code: FR

Ref legal event code: CT

Free format text: PRODUCT NAME: ACIDE OBETICHOLIQUE; REGISTRATION NO/DATE: EU/1/16/1139 20161212

Spc suppl protection certif: 17C0003

Filing date: 20170607

Extension date: 20270220

REG Reference to a national code

Ref country code: DE

Ref legal event code: R069

Ref document number: 60205891

Country of ref document: DE

Free format text: PRODUCT NAME: OBETICHOLSAEURE; REGISTRATION NO/DATE: EU/1/16/1139 20161212

Spc suppl protection certif: 122017000034

Filing date: 20170522

Expiry date: 20220222

Extension date: 20270221

REG Reference to a national code

Ref country code: FR

Ref legal event code: AV

Effective date: 20180528

REG Reference to a national code

Ref country code: IE

Ref legal event code: SPCG

Free format text: PRODUCT NAME: OBETICHOLIC ACID; REGISTRATION NO/DATE: EU/1/16/1139/001 EU/1/16/1139/002 20161212

Spc suppl protection certif: 2017/019

Extension date: 20270220

Effective date: 20180801

REG Reference to a national code

Ref country code: CH

Ref legal event code: SPCF

Free format text: PRODUCT NAME: ACIDUM OBETICHOLICUM; REGISTRATION NO/DATE: SWISSMEDIC 66530 01.06.2018

Filing date: 20180814

REG Reference to a national code

Ref country code: FI

Ref legal event code: SPCG

Spc suppl protection certif: 598

Extension date: 20270221

REG Reference to a national code

Ref country code: CH

Ref legal event code: SPCG

Free format text: PRODUCT NAME: ACIDUM OBETICHOLICUM; REGISTRATION NO/DATE: SWISSMEDIC-ZULASSUNG 66530 01.06.2018

Spc suppl protection certif: C01392714/01

Filing date: 20180814

Extension date: 20270220

REG Reference to a national code

Ref country code: BE

Ref legal event code: SPCF

Free format text: PRODUCT NAME: ACIDE OBETICHOLIQUE; AUTHORISATION NUMBER AND DATE: EU/1/16/1139 20161215

Spc suppl protection certif: 2017C/018

Filing date: 20170606

Expiry date: 20220221

Ref country code: BE

Ref legal event code: SPCG

Free format text: PRODUCT NAME: ACIDE OBETICHOLIQUE; AUTHORISATION NUMBER AND DATE: EU/1/16/1139 20161215

Spc suppl protection certif: 2017C/018

Filing date: 20170606

Expiry date: 20220221

Extension date: 20270221

Effective date: 20210204

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20210219

Year of fee payment: 20

Ref country code: CH

Payment date: 20210303

Year of fee payment: 20

Ref country code: NL

Payment date: 20210224

Year of fee payment: 20

Ref country code: LU

Payment date: 20210225

Year of fee payment: 20

Ref country code: PT

Payment date: 20210204

Year of fee payment: 20

Ref country code: MC

Payment date: 20210204

Year of fee payment: 20

Ref country code: IE

Payment date: 20210225

Year of fee payment: 20

Ref country code: GR

Payment date: 20210225

Year of fee payment: 20

Ref country code: FR

Payment date: 20210223

Year of fee payment: 20

Ref country code: FI

Payment date: 20210225

Year of fee payment: 20

Ref country code: CY

Payment date: 20210205

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20210225

Year of fee payment: 20

Ref country code: SE

Payment date: 20210225

Year of fee payment: 20

Ref country code: TR

Payment date: 20210209

Year of fee payment: 20

Ref country code: BE

Payment date: 20210225

Year of fee payment: 20

Ref country code: AT

Payment date: 20210203

Year of fee payment: 20

Ref country code: ES

Payment date: 20210301

Year of fee payment: 20

Ref country code: GB

Payment date: 20210225

Year of fee payment: 20

Ref country code: DK

Payment date: 20210225

Year of fee payment: 20

REG Reference to a national code

Ref country code: GB

Ref legal event code: CTFG

Free format text: PRODUCT NAME: OBETICHOLIC ACID; REGISTERED: UK EU/1/16/1139/001- NI 20161215; UK EU/1/16/1139/002-NI 20161215; UK PLGB 48025/0002 20161215; UK PLGB 48025/0003 20161215

Spc suppl protection certif: SPC/GB17/033

Filing date: 20170520

Extension date: 20270220

Effective date: 20210719

REG Reference to a national code

Ref country code: DE

Ref legal event code: R071

Ref document number: 60205891

Country of ref document: DE

REG Reference to a national code

Ref country code: FR

Ref legal event code: SPAY

Free format text: PRODUCT NAME: ACIDE OBETICHOLIQUE; REGISTRATION NO/DATE: EU/1/16/1139 20161212

Spc suppl protection certif: 17C0003

Filing date: 20170607

Year of fee payment: 1

Extension date: 20270220

Ref country code: NL

Ref legal event code: MK

Effective date: 20220220

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

Ref country code: DK

Ref legal event code: EUP

Expiry date: 20220221

REG Reference to a national code

Ref country code: BE

Ref legal event code: MK

Effective date: 20220221

REG Reference to a national code

Ref country code: GB

Ref legal event code: PE20

Expiry date: 20220220

Ref country code: GB

Ref legal event code: CTFE

Free format text: PRODUCT NAME: OBETICHOLIC ACID; REGISTERED: UK EU/1/16/1139/001- NI 20161215; UK EU/1/16/1139/002-NI 20161215; UK PLGB 48025/0002 20161215; UK PLGB 48025/0003 20161215

Spc suppl protection certif: SPC/GB17/033

Filing date: 20170520

Expiry date: 20220221

Extension date: 20270220

REG Reference to a national code

Ref country code: FI

Ref legal event code: MAE

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: IE

Ref legal event code: MK9A

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK07

Ref document number: 303399

Country of ref document: AT

Kind code of ref document: T

Effective date: 20220221

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20220221

Ref country code: GB

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20220220

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20220301

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20220222

REG Reference to a national code

Ref country code: FR

Ref legal event code: SPAY

Free format text: PRODUCT NAME: ACIDE OBETICHOLIQUE; REGISTRATION NO/DATE: EU/1/16/1139 20161212

Spc suppl protection certif: 17C0003

Filing date: 20170607

Year of fee payment: 2

Extension date: 20270220

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230525

REG Reference to a national code

Ref country code: FR

Ref legal event code: SPAY

Free format text: PRODUCT NAME: ACIDE OBETICHOLIQUE; REGISTRATION NO/DATE: EU/1/16/1139 20161212

Spc suppl protection certif: 17C0003

Filing date: 20170607

Year of fee payment: 3

Extension date: 20270220